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, 15 (12), e1008177
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Deep Sequence Analysis of HIV Adaptation Following Vertical Transmission Reveals the Impact of Immune Pressure on the Evolution of HIV

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Deep Sequence Analysis of HIV Adaptation Following Vertical Transmission Reveals the Impact of Immune Pressure on the Evolution of HIV

Jennifer Currenti et al. PLoS Pathog.

Abstract

Human immunodeficiency virus (HIV) can adapt to an individual's T cell immune response via genomic mutations that affect antigen recognition and impact disease outcome. These viral adaptations are specific to the host's human leucocyte antigen (HLA) alleles, as these molecules determine which peptides are presented to T cells. As HLA molecules are highly polymorphic at the population level, horizontal transmission events are most commonly between HLA-mismatched donor/recipient pairs, representing new immune selection environments for the transmitted virus. In this study, we utilised a deep sequencing approach to determine the HIV quasispecies in 26 mother-to-child transmission pairs where the potential for founder viruses to be pre-adapted is high due to the pairs being haplo-identical at HLA loci. This scenario allowed the assessment of specific HIV adaptations following transmission in either a non-selective immune environment, due to recipient HLA mismatched to original selecting HLA, or a selective immune environment, mediated by matched donor/recipient HLA. We show that the pattern of reversion or fixation of HIV adaptations following transmission provides insight into the replicative cost, and likely compensatory networks, associated with specific adaptations in vivo. Furthermore, although transmitted viruses were commonly heavily pre-adapted to the child's HLA genotype, we found evidence of de novo post-transmission adaptation, representing new epitopes targeted by the child's T cell response. High-resolution analysis of HIV adaptation is relevant when considering vaccine and cure strategies for individuals exposed to adapted viruses via transmission or reactivated from reservoirs.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Adaptations can be transmitted, but their maintenance or reversion is dependent on the immune selection environment of the recipient and replicative cost.
In this cohort the original source of HIV in the mother is unknown and is depicted as either the child’s father or another individual (represented by circulating adaptation). In this model, the original source virus adapts to the immune selection environment in the mother before being transmitted to the child. While in the mother, HIV adaptations corresponding to the child’s paternal HLA allele are in a non-selective immune environment. Such adaptations may revert (scenario 5) to the non-adapted form due to a replicative cost or may be maintained (scenario 4) if the adaptation has no replicative cost or has linked compensatory mutations. De novo adaptations corresponding to the maternal HLA alleles may arise in the mother’s autologous virus due to immune selection pressure. During transmission of the virus from the mother to the child there is a bottleneck event with the resultant founder viruses in the child likely carrying HIV adaptations relevant to both maternal and paternal HLA alleles. The maintenance (scenario 1 or 4), reversion (scenario 2 or 5), and selection of de novo adaptations (scenario 3) in the child’s virus will be dependent on the new immune selection environment and/or replicative cost of the adaptations.
Fig 2
Fig 2
(A) Maximum likelihood phylogenetic tree of Gag majority sequences confirms mother-to-child transmission (mother, M = closed diamond; child, C = open diamond) with no evidence of larger transmission networks within cohort (see S1B and S1C Fig for Pol and Nef). (B) Intra-individual genetic diversity of Gag quasispecies was significantly higher in the mother than the child (N = 26, p = 0.0001; paired t-test) with similar results obtained for Pol and Nef (see S1E and S1F Fig). Data are represented as mean ± SE. (C) Significant positive correlation across all proteins for nucleotide differences (%) between mother/child pairs and age at sampling (time since transmission) (N = 23, p = 0.007; mixed-effects linear regression model). There was a significant difference between the nucleotide differences (%) for the different proteins (N = 23, p<0.0001; linear regression). p<0.001 (***).
Fig 3
Fig 3. Autologous virus is adapted in both mother and child.
The proportion of known HIV adaptations observed in the autologous virus of mother/child pairs. (A) Adaptations were separated into three groups: 1) shared maternal HLA alleles present in both mother and child; 2) paternal HLA alleles only present in the child; and 3) mother-only HLA alleles present only in the mother. (B) Adaptations based on location within HIV proteins Gag, Pol, and Nef. (C) Adaptations sorted by HLA locus. All analyses were performed using mixed-effects logistic regression incorporating HLA inheritance, HIV protein, and HLA locus. Data are represented as mean ± SE. N = 23, p<0.0001 (****), p<0.001 (***), p<0.01 (**), p<0.05 (*).
Fig 4
Fig 4. Adaptation dynamics following transmission affected by bottleneck event, immune selection pressure, replicative cost and drift.
(A) The % of quasispecies for all adapted amino acids in Gag, Pol, and Nef in the mother/child pairs (N = 633) were plotted on the x-axis for the mother, and the y-axis for the child. Points are superimposed on each other and the color range reflects number of superimposed points with red (maximum, max) and blue (minimum, min). ‘Maintained’ adaptations are present in the top right corner (≥90% in the child), ‘reverted’ in the bottom right corner (<10% in the child), and ‘de novo’ adaptations along the y-axis (<10% in the mother), with respect to the child. (B) Adaptations that are potentially under immune selection pressure in both the mother and child (shared maternal HLA; N = 249; scenarios 1–3 in the child from Fig 1). (C) Adaptations that are in a non-selective immune environment in the mother, but potential selective environment in the child (paternal HLA; N = 181; scenarios 4–5 for the mother and 1–3 for the child from Fig 1). (D) Adaptations that are potentially under a selective environment in the mother, but a non-selective immune environment in the child (mother-only HLA; N = 203; scenarios 1–3 for the mother and 4–5 for the child from Fig 1). In all panels, percentages denote adaptations that are present in that quadrant for that grouping. Panels B-D also indicate the likely influence of selection on, and replicative cost of (theoretical), adaptations along the axes.
Fig 5
Fig 5. De novo HIV adaptations occur in the child following transmission.
(A) Significantly higher proportion of de novo adaptations were relevant to the paternal HLA allele than both maternal HLA alleles. (B) Gag and Nef had significantly more de novo adaptations relative to Pol. (C) There was no significant difference between de novo adaptations relevant to the different HLA loci. All analyses were performed as in Fig 4. N = 23, p<0.01 (**), p<0.05 (*). Data are represented as mean ± SE.
Fig 6
Fig 6. Adaptation scores are correlated with clinical measures of disease outcome in the mother, but not the child.
In the mother, adaptation scores positively correlated with viral load (N = 21, Spearman’s r = 0.44, p = 0.05; A), and negatively correlated with CD4+ T cell % (N = 23, Spearman’s r = −0.50, p = 0.02; C). In the child, there was no correlation between adaptation scores and viral load (N = 14, p = 0.7; B) or CD4+ T cell % (N = 23, p = 0.9; D). 95% confidence intervals are shown.
Fig 7
Fig 7. HIV-infected children responded to a broad array of Gag peptides but had a limited response to optimal CD8+ T cell epitopes, including immunodominant T cell epitopes.
(A) There was a significantly higher response in the mother than the child for HLA-A-restricted optimal CD8+ T cell epitopes (N = 13, p = 0.03; Wilcoxon signed-rank test) and a trend for HLA-B-restricted optimal CD8+ T cell epitopes (N = 15, p = 0.08). Data are represented as mean ± SE. (B) There was no difference in IFN-γ responses to a Gag peptide pool in the mother and child (N = 24, p>0.9).

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